Chronic lung diseases share common features of epithelial repair defects and fibroproliferation that contribute to loss of tissue homeostasis and deterioration of lung function. There is growing support for the notion that signaling changes between epithelial cells and fibroblasts are key factors that drive defective epithelial maintenance/repair and tissue remodeling. Goals of this proposal are to identify small molecule regulators of epithelial-fibroblast interaction that have potential to promote epithelial regeneration. We have developed a novel in vitro model to investigate the behavior of lung epithelial progenitor cells in a controlled culture environment. Expansion of epithelial progenitor cells in this in vitro model is dependent upon stromal cell interactions that recapitulate cell-cell interactions in the intact lung. This in vitro assay will be used to screen a library of FDA approved compounds for their ability to regulate growth of epithelial progenitor cells (Aim 1). Secondary screening will be performed to determine whether the identified compounds have broad spectrum or selective activity towards three distinct progenitor cell types of mouse airways (Aim 2). Results will provide new insights into signaling interactions between epithelial progenitor cells and lung fibroblasts, and will identify candidate drugs with potential to enhance epithelial repair and restore lung function to patients with chronic lung disease.